Stroke is the second leading cause of death globally. Ischemic stroke which accounts for up to 90% of strokes in the USA, is the clinical culmination of several complex and interacting biological processes, initiated by various genetic and environmental factors, thereby making ready analyses of its underlying mechanisms a challenge. Substantial amount of genetic risk for stroke remain unexplained. Moreover, genetic variants previously associated with stroke in African and European Americans could not be translated into clinical use because they have not been validated and functionally annotated. A better understanding of these unique factors is imperative for the formation of successful tailor-made interventions to mitigate this colossal burden. Due to its higher stroke heritability and resolution for fine mapping, the continental African population holds the aces to advancing stroke genomics but has never been included in stroke GWAS studies. The overall goal of SIBS-Genomics, is to discover, validate and functionally characterize novel genetic variants associated with ischemic stroke in people of African ancestry. SIBS Genomics will leverage several NIH-funded initiatives in the US and Africa led by SIBS Genomics investigators including REGARDS, SiGN, COMPASS, MEPI, THRIVES (U01NS079179), PINGS (NS094033) and the NINDS-funded Stroke Investigative Research and Educational Network (SIREN U54HG007479), the largest study of stroke in people of African ancestry. Indeed SIBS Genomics promises to substantially advance the global effort to discover the novel genetic loci for ischemic stroke thereby facilitating the understanding of the corresponding molecular mechanisms of ischemic stroke for numerous reasons: a) use of accurately phenotyped subjects with comprehensive covariate dataset (special stroke phenotyping software with patent developed in SIREN), b) use of a novel NIH-funded most effective chip for dense genome-wide association study in African ancestry, c) an unexplored population with substantially higher heritability and racial predilection of stroke; and higher resolution for fine-mapping due to its low linkage disequilibrium. d) and processing of samples for future whole genome sequencing and transomics analyses. The goal of SIBS Genomics will be accomplished using a novel multi-stage approach in a concise network of leading global content experts. Validation and functional annotation of genetic variants previously reported in Americans will be performed using data from continental Africans. Furthermore, discovery of novel variants will be sought in continental Africans and validated in African Americans (71% of whom migrated from West Africa); while Americans of diverse ancestries will be included in trans-ancestry meta-analyses. Overall, new clues on the molecular mechanisms of stroke will open new array of targeted biomarkers (for prediction, diagnosis, prognosis), and interventions (neuroprotective, treatment, prevention) for stroke. This unique transomics study will translate to efficient solutions for controlling the burden of stroke in American populations, especially African Americans in whom the burden remains disproportionately high.